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Author
Topic: Studies in monkeys may be next step in search for HIV cure by powerful infusion. (Read 5772 times)

(Reuters) - A powerful infusion of HIV-fighting antibodies beat back a potent form of the virus in monkeys and kept it at bay for weeks, U.S. government scientists and a team led by Harvard University found, offering a potential next step in the battle against human HIV.

The two studies, published on Wednesday in the journal Nature, involve the use of rare antibodies made by 10 percent to 20 percent of people with HIV that can neutralize a wide array of strains.

Such antibodies latch on to regions of the virus that are highly "conserved," meaning they are so critical to the virus that causes AIDS that they appear in nearly every HIV strain.

By attaching to the virus, they make it incapable of infecting other cells.

In the past decade, scientists have tried to make vaccines that could coax the body into making these same types of HIV-specific antibodies. But finding a way to make these complex antibodies has been challenging.

"These are the Ferraris of antibodies," said Dr Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, who led the larger of the two studies.

"Nobody, including ourselves, has been able to develop a vaccine that can generate immune responses that are even close."

In the studies, the teams instead tested these antibodies as a potential treatment for people infected with HIV. Both teams used rhesus monkeys with the Simian-human immunodeficiency virus, a monkey version of HIV.

Barouch's team studied the rare antibodies harvested from HIV-infected humans that were grown in large batches and could be infused at high doses. The team tested different combinations of antibodies in 35 infected monkeys.

The one that worked best was an antibody called PGT121.

"Basically, that antibody, given either alone or in combination, resulted in a dramatic effect," Barouch said.

PEOPLE NEXT?

The antibodies reduced the virus to undetectable levels in 16 of 18 monkeys within seven days, and kept it there for one to three months. In three animals with the lowest viral load at the time of treatment, the virus did not resurface.

A smaller study by scientists at the National Institute of Allergy and Infectious Diseases, a part of the National Institutes of Health, showed similar results.

Both teams say the approach should now be tested in people.

"All the data to date exist in the monkey model. We need to evaluate how these antibodies perform in humans infected with HIV," Barouch said.

His team did not test the antibody treatment in combination with antiretroviral treatments, the standard HIV drugs used by thousands of patients to control the virus.

But Barouch thinks such combinations would make sense because both treatments have different mechanisms of action.

While antiretroviral drugs only attack the machinery used by the HIV virus to make copies of itself, antibodies can directly attack free virus particles in the blood as well as in cells that are infected with the virus.

Barouch said researchers and drug companies are interested in the results, which could offer a next step toward a cure for the infection that causes AIDS.

In an interview on the Nature website, Dr Louis Picker of Oregon Health & Science University, who wrote a commentary on the research, said the study is "a baby step towards cure."

He said antiretroviral treatments, such as those made by Gilead Sciences and GlaxoSmithKline, reduce the ability of the HIV virus to replicate in the body by maybe 99.9 percent, but not 100 percent.

"This treatment on top of it may bring it to 100 percent," he said.

Still unclear is whether antibodies will also attack latent HIV cells that hide in the body and allow the virus to reappear when treatment stops.

"We haven't shown any cures," Barouch said. "However, we have shown the antibodies act not only on the virus in the bloodstream, but can also substantially reduce virus in tissues such as lymph nodes and the gut. Future research with these antibodies will help determine whether they might be part of a virus eradication or cure strategy."

Antibodies derived from the blood of HIV-infected people suppressed the virus in the blood of monkeys in two studies that suggest the experimental approach may improve AIDS therapy or point the way toward a cure.

One study showed that a single injection of antibodies reduced the simian, or monkey, version of HIV to undetectable levels in three to seven days -- much faster than regular AIDS drugs -- and the effect lasted for almost TWO MONTHS. The research, led by Dan Barouch, professor of medicine at Harvard Medical School, is published today online by the journal Nature.

The antibodies represent a new and potentially more powerful approach to treating a disease currently controlled by daily pills such as those made by Gilead Sciences Inc. (GILD) While those drugs have transformed HIV from a death sentence into a manageable disease, they don’t completely clear the virus from the body. The new antibodies attack HIV in areas the drugs don’t reach, suggesting they may have a role in curing a disease that has confounded scientists for 30 years.

“The antibodies themselves are very, very special,” said Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, a Harvard affiliate in Boston. “These antibodies should be explored for a variety of different clinical applications. Clearly where there’s going to be substantial interest is evaluating their potential role in cure.”

Thank you for posting this! Great stuff. Seems like you could stay on the ARVs to stop replication, then use these ABs to blast away at the reservoirs.

It's not unlike Picker's approach with the modified CMV -- use that to constantly get the body to create antibodies. Seems like this method is better for giving you the best type of antibody tho. Very interesting!

Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian–human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans."

The one thing I still don't understand: They've been identifying and experimenting with this kind of broadly neutralizing antibodies for quite a few years (early 90s?). What took them so long to get this result?

Anyway, since these antibodies seem to work much quicker that ART drugs, they might be promising for those few patients that are diagnosed while still undergoing seroconversion. If they kill all of the virus before it forms reservoirs, those patients might get as lucky as the recently cured baby, or at least as lucky as the French patients whose immune system is able to manage the virus without additional drugs.

I hope they'll start human trials soon. Should be a pretty straight forward process. After all, injecting antibodies into a patient is nothing new.

Quote

Still unclear is whether antibodies will also attack latent HIV cells that hide in the body and allow the virus to reappear when treatment stops.

I'm more skeptic about that part. I don't see how an antibody could possibly detect a small piece of viral DNA within the human DNA in the nucleus of a latent cell. So, just as with the ART drugs, they only get active once the latent cell wakes up and produces virus particles. I don't know, perhaps a new shot of those antibodies is needed once every few months to keep the levels up until all reservoirs are depleted (which might take many years).What do you think?

"I don't see how an antibody could possibly detect a small piece of viral DNA within the human DNA in the nucleus of a latent cell. So, just as with the ART drugs, they only get active once the latent cell wakes up and produces virus particles. I don't know, perhaps a new shot of those antibodies is needed once every few months to keep the levels up until all reservoirs are depleted (which might take many years).What do you think?"

Don't think an ab is going to do anything to a latent cell, but since 3 monkeys have been able to control their VL ala elite controler for up to 8 months means that these ab hit something our current drugs can't hit. Perhaps they hit the so called sanctuaries?

Anyways, from what I have read these ab are more potent then any antivirals we have thus far...and surely without any SE or toxicities...and with a long half-life. Perhaps an infusion/injection every 2/3 months or so will do. Have also read that the pharmaceutical companies REALLY want to start clinical trials. That is algo good.

Saw a video on youtube a few weeks ago were David Baltimore ( Nobel prize winner for discovering reverse transcriptase) was talking about using gene therapy to get muscle cells ( leg, arm?) to start to produce these kinds of ab. If we can get a vector into a muscle cell they can start to produce these ab...so we basically bypass the immune system all together. If this can be done, and if we get the correct Ab, we will all be elite controllers.

David Baltimore has already demonstrated with humanizad rats that this works...he called it immunoprophylaxis I think.

Yep, I agree with all your conclusions. If it works that well in humans we might all become elite controllers.I don't see any reason why this shouldn't work as effectively in humans as it does in monkeys.

It's the first time in months that I get that excited about a new piece of HIV research.

I just read in another article that currently, it is extremely expensive to produce these kind of antibodies (much more than what the current ART regimes cost per month). So, I am wondering by how much they will be able to lower the costs, once they scale up the production.

These antibodies may be able to eradicate HIV from the body (they haven't been able to detect HIV in some of the monkeys still, perhaps leading to functional cure!). This isn't just test tube results, either... I hope they get started on humans soon.

In my own personal battlefield news, my CD4 shot up to 164 and my doctor now considers me "undetectable" (though the 34 copies in my blood are 34 too many for me). My molluscum has melted away, and I'm feeling a bit better. I have dinner with my (?)boyfriend who I haven't seen since this sh*tstorm started. Who knows if we can rekindle something. I still love him, and I think he still loves me. I ran into him at work the other day and had to hold back tears.

Antibody drugs can be spectacularly effective when attacking something foreign (a virus)... this is really grounds for optimism. Anything that has 3 log decline in 7 days is miraculous. These were used without any ARVs on board.... so if viral replication is already suppressed by ARVs, these antibodies could attack virus that's not replicating, potentially eliminating reservoirs...Pretty cool. It's another new door to a potential eradication protocol.

Antibody drugs are generally expensive to make compared to small molecule drugs, but the high cost of ARV treatment and its lifelong nature will help accelerate the development of these drugs. Antibodies are by nature not any more expensive to make and distribute than insulin... they're just proteins.

A shot of Lucentis costs ~$1000-2000 US, a dose of Avastin for chemo costs around $1000 as well. Enbrel is taken very frequently for rheumatoid arthritis and costs 24,000 a year, which is what Atripla or Stribild costs per year in the US. If one injection can work for 3 months, it's potentially cost effective. If it can be potentially curative it's DEFINITELY cost-effective.

Why go get injected every three months with these Ab when your body can make them via VIP. This process totally bypasses the immune system all together. And it has worked with humanizad mice already and cost wont be suck an issue too: Here:

Someday we will be able to manipulate the immune system, but that's still difficult. Right now millions of people around the world are taking antibody-based drugs. The exciting part about this study is that the antibodies were used without any other antiretroviral drugs and produced a sustained response in some of the monkeys. Who knows what it will do combined with a HIV regimen... it might even result in functional cure.

The standard ARVs are coming off patent and other countries are flooding the market with cheaper versions.

It's not hard to see big pharma wanting the next big thing. Seems to me there's going to be a lot of interest in this as there will be a strong financial incentive to bring something new to the market.

True. And I also think big Pharma does'nt have the same control it did 10 years ago. Now there are many smaller and more forward thinking biotech companies that can and are going to try everything they can to come out with a form of cure, call this erradication, functional or even, why not, transform us into elite controllers.

Hope I don't sound mad repeating this again, but I think David Baltimore's VIP might be able to help. Why get infused every few months when you can have your muscle cells produce mABs constantly?

I think its worth pointing out this ... Some people think a cure is being held up or withheld in some cases and I really do not think its true , not even a little bit .

I know of a researcher in a major hospital who has contributed to aids research since the beginning and was the doctor who designed and administered the clinical trials for what we know is the 3 drug combo . When he speaks about HIV and research he becomes emotional , its because aids research and a cure has been his life work , it means everything to him and I have never known a HIV negative person that wants a cure more than this man and its not ego or profit driven either .

I know that there are many other researchers too that would be crying fowl from the mountaintops if they thought a single treatment was being withheld , much less any science that could lead to a cure .

Jeff G: I agree and I have always thought that those that think that the cure for HIV has already been discovered and is being held back are scary to say the least; scientist are very competitive, and most I'd think would rather have the fame of discovering a cure for this than all the money big Pharma can give them.

Wolfhorn: are you positive--no pun intended--that gene therapy has not worked for ANY human disease? They have; google it. But I do agree that the antibody infusions will get to market before any gene therapy involving mABs. But don't know by how much. David Baltimore has a lot of clout and perhaps after reading about what the mABs have done to monkeys his team might be "putting two and two together" as we speak...one can dream right?

gene therapy is not approved to treat any human disease yet. that's the big problem. they've had limited success treating fatal diseases, so it's going to be hard to get approval for HIV when HAART works so well. antibodies are in wide use. i think it's a potential solution

i'm impatient and am more excited about antibody drugs that can eradicate the virus from me ASAP.

I think the virus that the monkeys were infected with was a SIV/HIV hybrid virus SHIV, and the antibodies they used were humanized antibodies to HIV.

The issue to gene therapy is the long road to approval, even after something is successfully demonstrated... the FDA is notoriously conservative and won't allow such therapies to be used until extensive testing is done, and the high potential cost will limit me (as an insured American) to use things that are approved in the US. The great thing about an antibody-based protocol is that antibody infusions are already standard of care for some diseases (e.g. wet macular degeneration) and so the FDA is likely to be less skittish about approving these therapies after successful trials. I think that antibody-based protocols are likely to be approved in less than 10 years, while gene therapy could take 15-20 yrs. Hopefully by that time there will be a vaccine as well.

David Baltimore's VIP---vectored immunoprophylaxis---which uses a viral vector to introduce genetic information into our muscle cells so that it can produce broad neutralizing antibodies (PG9) is scheduled to start soon in healthy adults. They have had a prophylactic vaccine in mind for this, but after the results of the monkey trials I think they should also test it as a therapeutic vaccine in HIV infected individuals.

David Baltimore's VIP---vectored immunoprophylaxis---which uses a viral vector to introduce genetic information into our muscle cells so that it can produce broad neutralizing antibodies (PG9) is scheduled to start soon in healthy adults.

Yeah, you are right, I can't find Baltimore's name either. And I just read that Baltimore was not the one to come up with this idea, it was Phillip Johnson from Children's Hospital of Philadelphia. When this came last year the media said it was Baltimore's idea. Anyways, Baltimore et al were the ones who named it VIP after their experiments.

CHOP is one of the institutions afiliated with this clinical trial using VIP.

Yeah, you are right, I can't find Baltimore's name either. And I just read that Baltimore was not the one to come up with this idea, it was Phillip Johnson from Children's Hospital of Philadelphia. When this came last year the media said it was Baltimore's idea. Anyways, Baltimore et al were the ones who named it VIP after their experiments.

CHOP is one of the institutions afiliated with this clinical trial using VIP.